Our overall objective is to solve the problem of how proteins fold into their native conformations and then (e.g., as enzymes) interact with substrates and other ligands. For this purpose, we are developing and applying experimental and theoretical techniques to provide an understanding of the internal interactions which stablize native proteins in aqueous solution. Besides using the conventional methods of protein physical chemistry (including circular dichroism and nuclear magnetic resonance), our emphasis here is on the use of laser-Raman spectroscopy, calorimetry, electric dichroism, dipole moments, statistical mechanics, and conformational energy calculations. These techniques are being applied to specific problems, involving the structures of polypeptides and proteins in solution, which are described in this proposal.